The present invention relates to a novel class of indole derivatives having affinity for the dopamine D4 receptor. The compounds have antagonistic effect at the dopamine D4 receptor and are therefore useful in the treatment of certain psychiatric and neurologic disorders, in particular psychoses. Some of the compounds also have affinity for the 5-HT2A and/or the 5-HT2C receptor and some of the compounds are serotonin reuptake inhibitors.
AT 332401 discloses compounds of the general formula 
wherein R is hydrogen or alkyl, R1 and R2 are hydrogen or alkyl, p is 2 or 3 and X1 is hydrogen, fluoro, chloro or bromo. The compounds are said to be useful as neuroleptics. The patent does not contain any experimental data.
WO 95/11680 relates to a broad class of compounds having antipsychotic activity. One group of compounds claimed are compounds having the formula 
wherein X1 is O, S, NH or NR2, Alk is alkylene, W1 is CH2, O, S or NH, and R is hydrogen, alkyl, alkoxy, hydroxy, carboxyl, halogen, amino, alkylamino, dialkylamino, nitro, alkylthio, trifluoromethoxy, cyano, acylamino, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, etc. The application does not explain any mechanism of action, but the compounds are said to have a reduced tendency to cause extrapyramidal side effects.
Dopamine D4 receptors belong to the dopamine D2 subfamily of receptors which is considered to be responsible for the antipsychotic effect of neuroleptics. The side effects of neuroleptic drugs which primarily exert their effect via antagonism of D2 receptors are known to be due to D2 receptor antagonism in the striatal regions of the brain. However, dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that selective antagonists of the dopamine D4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D4 than D2 receptors and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507-526, and Sanner Exp. Opin. Ther. Patents 1998, 8, 383-393).
A number of D4 ligands, which were postulated to be selective D4 receptor antagonists (L-745,879 and U-101958), have been shown to possess antipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135, 194-200). However, recently it has been reported that these compounds are partial D4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620). Furthermore, it was shown that clozapine, which is an effective antipsychotic, is a silent D4 antagonist (Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620).
Consequently, D4 ligands which are partial D4 receptor agonists or antagonists may have beneficial effects against psychoses.
Dopamine D4 antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78-84).
Furthermore, evidence for a genetic association between the xe2x80x9cprimarily inattentivexe2x80x9d subtype of attention deficit hyperactivity disorder (ADHD) and a tandem duplication polymorphism in the gene encoding the dopamine D4 receptor has been published (McCracken et al. Mol. Psychiatry 2000, 5, 531-536). This clearly indicates a link between the dopamine D4 receptor and ADHD, and ligands affecting this receptor may be useful for the treatment of this particular disorder.
Various effects are known with respect to compounds which are ligands at the different serotonin receptor subtypes. As regards the 5-HT2A receptor, which was previously referred to as the 5-HT2 receptor, the following effects have been reported, e.g.:
Antidepressive effect and improvement of the sleep quality (Meert et al. Drug. Dev. Res. 1989, 18, 119), reduction of the negative symptoms of schizophrenia and of extrapyramidal side effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders British J. Psychiatry 1989, 155 (suppl. 5), 33). Furthermore, selective 5-HT2A antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; xe2x80x9cMigrainexe2x80x94Current trends in research and treatmentxe2x80x9d; PJB Publications Ltd.; May 1991) and in the treatment of anxiety (Colpart et al. Psychopharmacology 1985, 86, 303-305 and Perregaard et al. Current Opinion in Therapeutic Patents 1993, 1, 101-128).
Some clinical studies implicate the 5-HT2 receptor subtype in aggressive behaviour. Furthermore, atypical serotonin-dopamine antagonist neuroleptics have 5-HT2 receptor antagonistic effect in addition to their dopamine blocking properties and have been reported to possess anti-aggressive behaviour (Connor et al. Exp. Opin. Ther. Patents 1998, 8(4), 350-351).
Recently, evidence has also accumulated which support the rationale for selective 5-HT2A antagonists as drugs capable of treating positive symptoms of psychosis (Leysen et al. Current Pharmaceutical Design 1997, 3, 367-390 and Carlsson Current Opinion in CPNS Investigational Drugs 2000, 2(1), 22-24).
Compounds which are 5-HT reuptake inhibitors are well-known antidepressant drugs.
5-HT2C ligands have been found to augment the effect of 5-HT reuptake inhibitors in microdialysis experiments and animal models, and compounds having 5-HT reuptake inhibiting effect combined with affinity for the 5-HT2C receptor may therefore be particularly useful for the treatment of depression and other disorders responsive to serotonin reuptake inhibitors (PCT application No. PCT/DK00/00671).
Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects at the 5-HT transporter may have the further benefit of improved effect on depressive and negative symptoms in schizophrenic patients. Compounds with combined effect at the dopamine D4 receptor and the 5-HT2A receptor may have the benefit of improved effect on positive and negative symptoms of schizophrenia and the benefit of effect on depressive and anxiety symptoms.
In particular, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.
The object of the present invention is to provide compounds that are partial agonists or antagonists at the dopamine D4 receptor and such compounds with combined effects at the dopamine D4 receptor, the 5-HT2A receptor, the 5-HT2C and/or the 5-HT transporter.
Accordingly, the present invention relates to novel compounds of the formula I 
wherein R1 is hydrogen or C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, hydroxy, thiol, C1-6-alkoxy, C1-6-alkylthio trifluoromethyl, trifluoromethylsulfonyl and C1-6-alkylsulfonyl, or R1 is aryl, aryl-C1-6-alkyl, heteroaryl, heteroaryl-C1-6-alkyl where the aryl and heteroaryl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl, or R1 is xe2x80x94NRxe2x80x2Rxe2x80x3 wherein Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen and C1-6-alkyl, aryl, aryl-C1-6-alkyl, heteroaryl and heteroaryl-C1-6-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, C1-6 alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl, and C1-6 alkylsulfonyl, or R1 is a saturated or partially saturated 5 to 6 membered ring containing one, two or three hetero atoms selected from O, S and a group Nxe2x80x94R9 wherein R9 is hydrogen or C1-6-alkyl optionally substituted with substituents selected from halogen, cyano, nitro, amino, C1-6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl;
W is a bond or W is an O, S, CO, CS, SO or SO2 group;
n is 0-6, m is 0-6 and n+m is 0-6; provided that when W is O, or S, nxe2x89xa72 and when W is CO, CS, SO or SO2, nxe2x89xa71;
X is C, CH or N, and the dotted line emanating from X indicates a bond when X is C and no bond when X is N or CH;
R2 is C1-6-alkyl;
R3-R7 are selected from hydrogen, halogen, cyano, nitro, amino, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6-alkylsulfonyl;
R8 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, aryl, aryl-C1-6-alkyl, acyl, thioacyl, C1-6-alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl, or a pharmaceutically acceptable acid addition salt thereof.
In one particular embodiment, the present invention relates to compounds wherein the indole is bound to X via position 3 of the indole.
In a further embodiment, the invention relates to such compounds wherein W is a bond. In particular, the present invention relates to compounds wherein n+m is 2.
In a further embodiment, the present invention relates to such compounds wherein R2 is a methyl group.
In another embodiment, the invention relates to compounds wherein the group xe2x80x94NHxe2x80x94COxe2x80x94R1 is attached to the phenyl group in a position para to the position of the R2 group.
In particular, the present invention relates to such compounds, wherein R1 is C1-6-alkyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, wherein the phenyl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, C1-6 alkoxy, C1-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl, or R1 is xe2x80x94NRxe2x80x2Rxe2x80x3 wherein one of Rxe2x80x2 and Rxe2x80x3 is selected from hydrogen and the other of Rxe2x80x2 and Rxe2x80x3 is selected from C1-6-alkyl, phenyl and phenyl-C1-6-alkyl, wherein the phenyl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, C1-6 alkoxy, C1-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl, or R1 is a tetrahydropyranyl, morpholino, thiomorpholino, piperidino, piperazino or a N-(hydroxy-C1-6-alkyl)piperazino group.
In a specific embodiment, the present invention relates to a compound selected from
3-(1-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole;
3-(1-{2-[5-(Cyclobutylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-chloro-1H-indole;
3-(1-{2-[2-Methyl-5-(3-methoxybenzoylamino)phenyl]ethyl}piperidin-4-yl)-5-chloro-1H-indole;
3-(1-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[2-Methyl-5-(pivaloylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[5-(Hexanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[5-(4-Fluorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[5-(3-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[2-Methyl-5-(pyridin-3-ylmethanoylamino)phenyl]ethyl }piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[2-Methyl-5-(3-phenylpropanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[2-Methyl-5-(3-Methyl-3-phenylureido)phenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole;
3-(1-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole;
3-(1-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole;
3-(1-{2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole;
3-(1-{2-[5-(3-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole;
3-(1-{2-[2-Methyl-5-(pyridin-3-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole;
3-[1-(2-{5-[2-(4-Methoxyphenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-6-chloro-1H-indole;
3-(1-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro-1H-indole;
3-[1-(2-{5-[(Cyclopentylmethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-6-chloro-1H-indole;
3-(1-{2-[2-Methyl-5-(morfolin-4-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-[1-(2-{5-[3-(4-Fluorophenyl)ureido]-2-methylphenyl}ethyl)piperidin-4-yl]-5-fluoro-1H-indole;
3-(1-{2-[5-(Hexanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H -indole;
3-(1-{2-[2-Methyl-5-(tetrahydropyran-4-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-(1-{2-[5-(4-Chlorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole;
3-(1-{2-[5-(3-Cyclohexylpropanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-1H-indole;
3-[1-(2-{5-[(3-Phenylpropanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole;
3-[1-(2-{5-[(2-Phenylethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole;
3-(1-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole;
3-(1-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole;
3-[1-(2-{5-[2-(4-Fluorophenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole;
3-[1-(2-{5-[2-(4-Methoxyphenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole;
3-[1-(2-{5-[(Cyclobutylmethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole;
3-(1-{2-[5-(benzoylamino)-2-Methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole;
3-(1-{2-[5-(4-Fluorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole;
3-(1-{2-[5-(4-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-1H-indole;
3-[1-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole;
3-[1-(2-{2-Methyl-5-[(pyridin-4-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole;
3-[1-(2-{2-Methyl-5-[(thiophen-2-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole;
3-[1-(2-{2-Methyl-5-[(thiophen-3-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole;
3-[1-(2-{2-Methyl-5-[(1-[1,2,3]thiadiazol-5-ylmethanoyl)amino]phenyl}ethyl) -piperidin-4-yl]-7-chloro-1H-indole;
3-{1-[2-(5-Acetylamino-2-methylphenyl)-ethyl]-3,6-dihydro-2H-pyridin-4-yl}-5-fluoro-1H-indole;
3-[1-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)-amino]-phenyl}-ethyl)-3,6-dihydro -2H-pyridin-4-yl]-5-fluoro-1H-indole;
3-[1-(2-{5-[(4-Fluorophenylmethanoyl)-amino]-2-methylphenyl}-ethyl)-3,6-dihydro -2H-pyridin-4-yl]-5-fluoro-1H-indole;
3-{1-[2-(5-Acetylamino-2-methylphenyl)-ethyl]-3,6-dihydro-2H-pyridin-4-yl}-7-chloro-1H-indole;
3-[1-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)-amino]-phenyl}-ethyl)-3,6-dihydro -2H-pyridin-4-yl]-7-chloro-1H-indole and
3-[1-(2-{5-[(4-Fluorophenylmethanoyl)-amino]-2-methylphenyl}-ethyl)-3,6-dihydro -2H-pyridin-4-yl]-7-chloro-1H-indole or a pharmaceutically acceptable salt thereof.
The compounds of the invention are partial agonists or antagonists at the dopamine D4 receptors. Many compounds have combined effect at dopamine D4 receptors and the 5-HT2A receptor, the 5-HT2C receptor and/or 5-HT reuptake inhibiting effect.
Accordingly, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ADHD and in the improvement of sleep.
In particular, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.
In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect, the present invention provides the use of a compound of formula I as defined above or an acid addition salt thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.
The compounds of general formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention.
The term C1-6-alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, C2-6-alkenyl and C2-6-alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
The terms C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkylamino, C1-6-alkylcarbonyl, and the like, designate such groups in which the alkyl group is C1-6 alkyl as defined above. The term C3-8-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.
Halogen means fluoro, chloro, bromo or iodo.
As used herein, the term acyl refers to a formyl, C1-6-alkylcarbonyl, arylcarbonyl, aryl-C1-6-alkylcarbonyl, C3-8-cycloalkylcarbonyl or a C3-8-cycloalkyl-C1-6-alkyl-carbonyl group and the term thioacyl is the corresponding acyl group in which the carbonyl group is replaced with a thiocarbonyl group.
The term aryl refers to a carbocyclic aromatic group, such as phenyl, or naphthyl, in particular phenyl.
The term heteroaryl refers to 5 membered monocyclic rings such as 1H-tetrazolyl, 3H-1,2,3-oxathiazolyl, 3H-1,2,4-oxathiazolyl, 3H-1,2,5-oxathiazolyl, 1,3,2-oxathiazolyl, 1,3,4-oxathiazolyl, 1,4,2-oxathiazolyl, 3H-1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,4,2-dioxazolyl, 3H-1,2,3-dithiazolyl, 3H-1,2,4-dithiazolyl, 1,3,2-dithiazolyl, 1,4,2-dithiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1H-imidazolyl, 1H-pyrazolyl, 1H-pyrrolyl, furanyl, thienyl, 1H-pentazole, 6-membered monocyclic rings such as 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, 4H-1,3,5-oxathiazinyl, 1,4,2-oxathiazinyl, 1,4,3-oxathiazinyl, 1,2,3-dioxazinyl, 1,2,4-dioxazinyl, 4H-1,3,2-dioxazinyl, 4H-1,3,5-dioxazinyl, 1,4,2-dioxazinyl, 2H-1,5,2-dioxazinyl, 1,2,3-dithiazinyl, 1,2,4-dithiazinyl, 4H-1,3,2-dithiazinyl, 4H-1,3,5-dithiazinyl, 1,4,2-dithiazinyl, 2H-1,5,2-dithiazinyl, 2H-1,2,3-oxadiazinyl, 2H-1,2,4-oxadiazinyl, 2H-1,2,5-oxadiazinyl, 2H-1,2,6-oxadiazinyl, 2H-1,3,4-oxadiazinyl, 2H-1,3,5-oxadiazinyl, 2H-1,2,3-thiadiazinyl, 2H-1,2,4-thiadiazinyl, 2H-1,2,5-thiadiazinyl, 2H-1,2,6-thiadiazinyl, 2H-1,3,4-thiadiazinyl, 2H-1,3,5-thiadiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-1,2-oxazinyl, 2H-1,3-oxazinyl, 2H-1,4-oxazinyl, 2H-1,2-thiazinyl, 2H-1,3-thiazinyl, 2H-1,4thiazinyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, 2H-pyranyl, 2H-thiinyl, or bicyclic rings such as 3H-1,2,3-benzoxathiazolyl, 1,3,2-benzodioxazolyl, 3H-1,2,3-benzodithiazolyl, 1,3,2-benzodithiazolyl, benzfurazanyl, 1,2,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, 1H-benzotriazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl, 1H-benzimidazolyl, 1H-indazolyl, 3H-1,2-benzoxathiolyl, 1,3-benzoxathiolyl, 3H-2,1-benzoxathiolyl, 3H-1,2-benzodioxolyl, 1,3-benzodioxolyl 3H-1,2-benzodithiolyl, 1,3-benzodithiolyl, 1H-indolyl, 2H-isoindolyl, benzofuranyl, isobenzofuranyl, 1-benzothienyl, 2-benzothienyl, 1H-2,1-benzoxazinyl, 1H-2,3-benzoxazinyl, 2H-1,2-benzoxazinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 2H-3,1-benzoxazinyl, 1H-2,1-benzothiazinyl, 1H-2,3-benzothiazinyl, 2H-1,2-benzothiazinyl, 2H-1,3-benzothiazinyl, 2H-1,4-benzothiazinyl, 2H-3,1-benzothiazinyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, isoquinolyl, quinolyl, 1H-2-benzopyranyl, 2H-1-benzopyranyl, 1H-2-benzothiopyranyl or 2H-1-benzothiopyranyl.
R1 meaning a saturated or partially saturated 5- to 6-membered ring containing one or two hetero atoms selected from O, S or a group Nxe2x80x94R9 includes groups wherein R1 is a group xe2x80x94CRaRb and groups wherein R1 is xe2x80x94NRaRb wherein Ra and Rb together form a 5- to 6-membered saturated or partially saturated ring optionally containing an additional Nxe2x80x94R9 group or an O or S atom, e.g groups such as piperidinyl, piperazinyl, N-(hydroxy-C1-6-alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrofuranyl, etc.
The acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.
The total daily dose is usually in the range of about 0.05-500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.
The compounds of the invention may be prepared as follows:
1) Alkylating a piperazine, piperidine or tetrahydropyridine of formula II with an alkylating derivative of formula III: 
xe2x80x83wherein R1-R8, X, W, n, m and the dotted line are as previously defined, and L is a leaving group such as e.g. halogen, mesylate or tosylate;
2) Reductive alkylation of an amine of formula II with a reagent of formula IV: 
xe2x80x83wherein R1-R8, X, W, n, m and the dotted line are as previously defined, and E is an aldehyde or an activated carboxylic acid;
3) Reducing the double bond in the tetrahydropyridinyl ring in derivatives of formula V: 
xe2x80x83wherein R1-R8, W, n and m are as previously defined;
4) Acylating an amine of formula VI 
xe2x80x83wherein R1-R8, X, W, n, m and the dotted line are as previously defined by the use of a carboxylic acid and a coupling reagent, an activated ester, an acid chloride, an isocyanate, a carbamoyl chloride or a by a two-step procedure by treatment with phosgene followed by addition of an amine;
5) Cleaving a polymer bound derivative of formula VII 
xe2x80x83wherein R1-R7, X, W, n and m are as previously defined and Rxe2x80x2OH is hydroxyethyl or hydroxymethyl polystyrene, Wang resin or analogous polyethylene glycol polystyrene resins; whereupon the compound of Formula I is isolated as the free base or a pharmaceutically acceptable acid addition salt thereof.
The alkylation according to method 1) is conveniently performed in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the alkylation can be performed at a fixed temperature which is different from the boiling point, in one of the above-mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or N-methylpyrrolidin-2-one (NMP), preferably in the presence of a base. The synthesis of the amines of formula II, 3-(piperidin-4-yl)-1H-indoles and 3-(3,6-dihydro-2H-pyridin-4-yl)-1H-indoles, has been described in the literature (see EP-A1-465398).
The alkylating derivatives of formula III are prepared by nitration of the alkyl-substituted phenylacetic acids followed by reduction of the nitro group, e.g. with tin(II) chloride and functionalization of the produced amino group. The carboxylic acid is subsequently reduced to the corresponding alcohol, e.g. by treatment with borane followed by conversion of the alcohol to a leaving group, e.g. by treatment with methane sulfonyl chloride or thionyl bromide.
The reductive alkylation according to method 2) is performed by standard literature methods. The reaction can be performed in two steps, e.g. coupling of amines of formula II with reagent of formula IV by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with a coupling reagent such as e.g. dicyclohexyl carbodiimide, followed by reduction of the resulting amide with lithium aluminium hydride or alane. The carboxylic acid of formula IV is prepared by nitration of the alkyl-substituted phenylacetic acid followed by reduction of the nitro group, e.g. with tin(II) chloride and finally functionalization of the resulting amino group.
The reaction can also be performed by a standard one-pot procedure, e.g. using a reductive amination of amines of formula II and aldehydes of formula IV. The aldehydes of formula IV are prepared by reduction of the before mentioned functionalized (aminophenyl)acetic acid by treatment with a reducing agent such as e.g. borane. The resulting alcohol is converted to the corresponding aldehyde by standard oxidation methods, e.g. pyridinium chlorochromate.
The reduction of the double bond according to method 3) is generally performed by catalytic hydrogenation at low pressure ( less than 3 atm.) in a Parr apparatus, or by using reducing agents such as diborane or hydroboric derivatives as produced in situ from NaBH4 in trifluoroacetic acid in inert solvents such as tetrahydrofuran (THF), dioxane or diethyl ether.
The acylation according to method 4) is conveniently performed by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with coupling reagents such as e.g. dicyclohexyl carbodiimide. When the acylation produces urea derivatives, the acylating reagent is carbamoyl chlorides, isocyanates or a two-step procedure consisting of treatment with phosgene followed by addition of an amine.
The intermediate compounds of formula VI are prepared as described in methods 1) and 2).
The derivatives of structure VII are prepared by means of a solid phase synthesis sequence as outlined below. The final product was cleaved from the resin according to method 5) using diluted sodium methoxide in a methanol/tetrahydrofuran mixture at ambient temperature. The first building block, VIII, prepared by tert-butoxycarbonyl protection of compounds of formula II, which is prepared by methods obvious to the chemist skilled in the art (see also EP-A1-465398), is generally attached to the resin (e.g. polystyrene bound ethyl 4-nitrophenyl carbonate) using base e.g. N,N-dimethylaminopyridine and N,N-diisopropylethylamine at elevated temperature (e.g. 50-100xc2x0 C.) in an aprotic solvent (e.g. DMF or DMSO). After deprotection of compound IX by trifluoroacetic acid, the second diversifying building block is introduced by alkylation of compound X whereby compound XI is formed. The alkylating reagent is prepared by nitration of alkylsubstituted phenylacetic acid by standard nitration procedures followed by reduction of the carboxylic acid, e.g. by treatment with borane in tetrahydrofurane and finally converting the produced alcohol to a leaving group, e.g. by treatment with methanesulfonyl chloride in dichloromethane and triethylamine. The alkylation is performed at elevated temperature (50-100xc2x0 C.) in an aprotic solvent such as DMF, acetone or acetonitrile leading to resin XI. After reduction of the nitro group, e.g. by treatment with tin(II) chloride in DMF, the third diversifying building block is introduced by standard acylation procedures, e.g. addition of an acid chloride, isocyanate or carbamoyl chloride and base at low temperature in DMF, dichloromethane or acetonitrile. 
Experimental Section
Melting points were determined on a Bxc3xcchi SMP-20 apparatus and are uncorrected. Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (C18 column 4.6xc3x9730 mm with a particle size of 3.5 xcexcm) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 4 min at 2 mL/min. Purity was determined by integration of the UV trace (254 nm). The retention times, Rt, are expressed in minutes.
Mass spectra were obtained by an alternating scan method to give molecular weight information. The molecular ion, MH+, was obtained at low orifice voltage (5-20V) and fragmentation at high orifice voltage (100-200V).
Preparative LC-MS-separation was performed on the same instrument. The LC conditions (C18 column 20xc3x9750 mm with a particle size of 5 xcexcm) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by split-flow MS detection.
1H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) were used as solvents. TMS was used as internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, dq=double quartet, tt=triplet of triplets, m=multiplet. NMR signals corresponding to acidic protons are generally omitted. Content of water in crystalline compounds was determined by Karl Fischer titration. For column chromatography silica gel of type Kieselgel 60, 40-60 mesh ASTM was used. For ion-exchange chromatography (SCX, 1 g, Varian Mega Bond Elut(copyright), Chrompack cat. no. 220776). Prior use of the SCX-columns was pre-conditioned with 10% solution of acetic acid in methanol (3 mL).